KBTBD4-mediated reduction of MYC is critical for hematopoietic stem cell expansion upon UM171 treatment

Abstract

Ex vivo expansion of hematopoietic stem cells (HSCs) is gaining in importance for cell and gene therapy and requires a shift from dormancy state to activation and cycling. However, abnormal or excessive HSC activation results in reduced self-renewal ability and increased propensity for myeloid-biased differentiation. We now report that activation of the E3 ligase complex CRL3KBTBD4 by UM171 not only induces epigenetic changes through CoREST1 degradation but also controls chromatin bound MYC levels to prevent excessive activation and maintain lympho-myeloid potential of expanded populations. Furthermore, reconstitution activity and multipotency of UM171-treated HSC is specifically compromised when MYC levels are experimentally increased despite degradation of CoREST1.